Process for formation of pyrrolidine ring



United States Patent 3,238,196 PROCESS FOR FORMATION 0F PYRROLIDINE RINGWataru Nagata, Nishinomiya-shi, Hyogo, Tadao Terasawa, Talratsuiri-shi,Osaka, and Tsutomu Aoki, Amagasaki-shi, Hyogo, Japan, assignors toShionogi & Co.,

, Ltd., Osaka, Japan No Drawing. Filed Mar. 13, 1964, Ser. No. 351,822Claims priority, application Japan, Mar. 14, 1963, 38/ 14,295 8 Claims.(Cl. 260-2395) wherein X is a ketalated 0X0 group such as ethylenedioxy.

The present process comprises reducing a 'y-ketalated oxo nitrile havingthe partial structural Formula I with a hydrogenated aluminum compoundsuch as aluminum hydride, lithium aluminum hydride, sodium aluminumhydride and potassium aluminum hydride in an inert organic solvent suchas tetrahydrofuran, dioxane and diglyme (diethyleneglycol dimethylether) to produce the corresponding pyrrolidine compound having thepartial structural Formula II in a single step.

It is characteristic of the present invention to effect the aboveconversion by one step. For successful accomplishment of such one stepconversion, the reduction must be carried out under a drastic condition,i.e. using large excess of the hydrogenated aluminum compound at arelatively high temperature during a long period. The amount of thehydrogenated aluminum compound to be used is usually about 20 to 100moles, preferably about 40 to about 80 moles, to one mole of thestarting 'y-ketalated oxo nitrile (I). The reaction temperature may varywithin a range from about 60 C. up to a decomposition temperature of thehydrogenated aluminum compound. For instance, when lithium aluminumhydride is used as the reducing agent, the reaction temperature may befrom about 80 to about 110 C.

It is general knowledge that a ketal group is ordinarily not affected inthe course of reduction using a hydrogenated aluminum compound. In fact,ketalation has been widely adopted in the field of organic chemistry forprotection of a carbonyl group from reduction. However, under such adrastic condition as in the present reduction process, the protectingketal group is split ofl? simultaneously with formation of a bondbetween the ketal bearing carbon atom and the nitrogen atom of the aminogroup resulting from the original cyano group to constitute apyrrolidine ring. In addition, the reduction of a 'y-0X0 nitrile can noteffect such a pyrrolidine ring formation, and the previous ketalation ofthe y-oxo group is indispensable for production of the objectivepyrrolidine compound (II).

The present process can be generally and widely applied for formation ofa pyrrolidine ring in various organic compounds with a great advantageover conventional methods. For instance, Marshall et al. accomplishedthe conversion of a 'y-ketalated oxo nitrile, dl-3a-hydroxy-20-oxo-5fi-pregnane-l8-nitrile ethyleneketal, into the correspondingpyrrolidine compound, di-N-desmethyl-SB- conan-Bwol, by three steps,i.e. (a) reduction of the cyano group with lithium aluminum hydride toan amino group, (b) elimination of the protecting ketal group onhydrolysis with intramolecular dehydration to form a pyrroline ring and'(c) catalytic hydrogenation of the double bond of the pyrroline ring inthe presence of platinum oxide [Marshall et al.: J. Am. Chem. Soc. vol.84, p. 1485 (1962)]. The present process can realize such conversion inonly one step.

Presently-preferred embodiments of the present invention are shown inthe following examples. In these examples, abbreviations each has theconventional meaning: e.g., ml. millitre(s); mg. milligram=(s); g.gram(s); C., degrees centigrade; M.P., melting point.

Preparation of dl-N-desmethyl-Sa-conan-3,B-ol: To a suspension oflithium aluminum hydride (4.7 g.) in a mixture of anhydrous diglyme (130ml.) and anhydrous tetrahydrofuran ml.), there is added dropwise asolution of dl-3fl-hydroxy-ZO-oxo-Sot-pregnane-18-nitrile ethyleneketal(2.4 g.) in a mixture of anhydrous diglyme (50 ml.) and anhydroustetrahydrofuran (25 ml.) at room temperature (10 to 30 C.) The resultantmixture is heated at to C. for about 70 hours while stirring In thecourse of heating, lithium aluminum hydride (4.7 g.) is addedportionwise thereto every 24 hours. The reaction mixture is portionwiseadded to a mixture of ice and Water whereby excess of lithium aluminumhydride is decomposed. The resultant mixture is shaken with ether, Theether extract is washed with sodium chloride solution, dried overanhydrous sodium sulfate and the solvent removed by evaporation. Theresidue is crystallized from a mixture of tetrahydrofuran and ether togive dl-N-desmethyl-5zx-conan-3(3-01 (1.1 g.), which is furtherrecrystallized from a mixture of methanol and ether to give thin plates.M.P., 200 to 201 C.

IR: 11:31? emf 3473, 3258, 3123 Analysis.Calcd. for C H ON: C, 79.44; H,11.11; N, 4.41. Found: C, 79.00; H, 11.13; N, 4.62.

The starting material of this example, dl-Bfl-hydroxy-20-0xo-5oi-pregnane-18-nitrile ethyleneketal, is prepared from1,2,3,4,5,6,7,9,10,11a,12,8,13a-dodecahydro-2-fl-hydroxy-12-methyl-7-oxophenanthrene[Howell et al.: J.

Chem. Soc., p. 1607 (1959)] according to the following scheme:

Acylation with benzoyl chloride and pyridine Condensation withl-bromotoxopentane ethyleneketal in the presence of sodium hydrideHydrolysis with sodium carbonate IzI solution Reduction with lithium inliquid ammonia Deketalation with 1:1 acetic acid Cyclization withethanolic sodium hydroxide solution Hydrocyanation with triethyl alumiumand hydrogen cyanide The product of this example,dl-N-desmethy1-5m-conan- 38-01, is converted into dl-4-conen-3-oneaccording to the following scheme, the latter being known and useful asan intermediate in the synthesis of conessine [Marshai'iu et 211.: J.Am. Chem. Soc., vol. 84, p. 1485 (1962)]:

N-Methylation with formaldehyde and formic acid Oxidation with chromicacid in acetic acid 1) Brominntion with bromine in the presence ofhydrobromic acid in acetic acid.

2) Dehydrobromination with sodium iodide.

3) Deiodination with chromous chloride Preparation ofdl-N-desmethyl-5u-eonan-3fi-o1: To a suspension of lithiumaluminumhydride (12.0 g.) in a mixture of anhydrous diglyme (340 ml.) andanhydrous tetrahydrofuran (170 ml.), there is added dropwise a solutionof dl-3fi-hydroxy-ZO-oxo-Su-pregnane-18-nitrile ethyleneketal (6.1 g.)in a mixture of anhydrous diglyme (130 m1.) and anhydroustetrahydrofuran (65 ml.) at room temperature to 30 C.). The resultantmixture is heated at 95 to 100 C. for about 50 hours while stirring. Inthe course of heating, lithium aluminum hydride (12.0 g.) is addedportionwise thereto every 24 hours. The reaction mixture is allowed tostand at room temperature overnight and then treated as in Example 1 togive dl-N- desrnethyl-5a-conan-3 {3-01 3 .0 g.

Example 3 CH3 I13: o CH3 1 t o HO--- HO' Preparation ofdl-N-desmethyl-518-conan-3a-ol: To a suspension of lithium aluminumhydride (12.0 g.) in a mixture of anhydrous diglyme (340 m1.) andanhydrous tetrahydrofuran 170 ml.), there is added dropwise a solutionof d1 3a-hydroxy-ZO-oxo-SB-pregnane-18-nitrile ethyleneketal (5.8 g.) ina mixture of anhydrous diglyme (130 ml.) and anhydrous tetrahydrofuran(65 ml.) at room temperature (10 to 30 C.). The resultant mixture isheated around 100 C. for about 60 hours while stirring. In the course ofheating, lithium aluminum hydride (12.0 g.) is added portionwise theretoevery 24 hours. The reaction mixture is treated as in Example 1 to givedl-N-desmethyl--conan-3a-ol (2.8 g.).

The starting material of this example, d1-3OL-l1ydIOXY-20-oxo-5f3-pregnane-l8-nitrile ethyleneketal, is known. The product ofthis example, 'dl-N-desmethyl-5B-conan- 3a-o1, is also known and usefulas an intermediate in the synthesis of conessine [Marshall et al.: J.Am. Chem. Soc., vol. 84, p. 1485 (1962)].

What is claimed is:

1. A single step process for converting y-ketaIated oxopregnane nitrileinto the corresponding pyrrolidine compound, which consists essentiallyin treating the 'y-ketalated oxo nitrile aluminum hydride in an inertorganic solvent at a temperature from about C. up to decomposingtemperature of the aluminum hydride until the aforesaid correspondingpyrrolidine compound is formed.

2. A process according to claim 1, wherein the start ing -ketalatedoxo-pregnane nitrile is 3-hydroxy-20-oxopregnane-18-nitrileethyleneketal.

3. A process according to claim 1 wherein the alumirnurn hydride islithium aluminum hydride.

4. A process according to claim 2, wherein the aluminum hydride islithium aluminum hydride.

5. A process according to claim 1, wherein the molar ratio of starting'y-ketalated oxo nitrile to aluminum hydride is 1 to 20100.

6. A process according to claim 2, wherein the molar ratio of starting'y-ketalated oxo nitrile to aluminum hydride is 1 to 20-100.

7. A process according to claim 1, wherein the reaction temperature isfrom about to about C.

8. A process according to claim 2, wherein the reaction temperature isfrom about 80 to about 110 C.

No references cited.

LEWIS GOTTS, Primary Examiner.

1. A SINGLE STEP PROCESS FOR CONVERTING $-KETALATED OXOPREGNANE NITRILEINTO THE CORRESPONDING PYRROLIDINE COMPOUND, WHICH CONSISTS ESSENTIALLYIN TREATING THE $-KETALATED OXO NITRILE ALUMINUM HYDRIDE IN AN INERTORGANIC SOLVENT AT A TEMPERATURE FROM ABOUT 60*C. UP TO DECOMPOSINGTEMPERATURE OF THE ALUMINUM HYDRIDE UNTIL THE AFORESAID CORRESPONDINGPYRROLIDINE COMPOUND IS FORMED.